Phase I Study in Humans Evaluating the Safety of Rectus Sheath Implantation of Diffusion Chambers Encapsulating Autologous Malignant Glioma Cells Treated With Insulin-like Growth Factor Receptor-1 Antisense Oligodeoxynucleotide (IGF-1R/AS ODN) in 32 Patients With Newly Diagnosed Malignant Glioma
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Collect adverse events as a measure of safety and tolerability of IG-1R/ AS ODN
研究概览
简要总结
This human Phase 1 trial is a continuation of a Phase 1 trial which enrolled patients with recurrent gliomas (#TJU-14379-101) and which was designed after a previously conducted Phase 1 human trial at our institution. With certain modifications, it is intended to reproduce the safety results of the recurrent glioma previous trials as well as explore any objective clinical responses in newly diagnosed patients. Protocol 14379-101 is closed to accrual and Abbreviated Clinical Report is prepared for FDA submission. The safety profile for this protocol was quite favorable.
This treatment involves taking the patient's own tumor cells at surgery, treating them with an investigational new drug (an antisense molecule) designed to shut down a targeted surface receptor protein, and re-implanting the cells, now encapsulated in small diffusion chambers the size of a nickel in the patient's abdomen within 24 hours after the surgery. Loss of the surface receptor causes the tumor cells to die in a process called apoptosis. As the tumor cells die, they release small particles called exosomes, each full of tumor antigens. The investigators believe that these exosomes as well as the presence of the antisense molecule work together to activate the immune system against the tumor as they slowly diffuse out of the chamber. Immune cells are immediately available for activation outside of the chamber because a wound was created to implant these tumor cells and a foreign body (the chamber) is present in the wound. In this trial, a dose escalation of the therapeutic agent will involve an increase in both biodiffusion chamber number as well as the time the biodiffusion chambers remain implanted. The wound and the chamber fortify the initial immune response which eventually leads to the activation of immune system T cells that attack and eliminate the tumor. By training the immune system to recognize the tumor, the patient is also protected through immune surveillance from later tumor growth should the tumor recur. Compared to treatment alternatives for tumor recurrence, including a boost of further radiation and more chemotherapy, this treatment represents potentially greater benefit with fewer risks.
详细描述
This trial will be an adaptation of Protocol 101 which recently closed after rapid and complete accrual, now with an escalation of the induction vaccination in four cohorts. For practical purposes, a standard dose-escalation study is not possible with the current paradigm. Although the investigators may have identified a distinct bioactive byproduct of Insulin-like growth factor receptor-1 Antisense Oligodeoxynucleotide (IGF-1R/AS ODN)-induced tumor cell apoptosis (exosomes), it is difficult to perform a dose escalation in a typical fashion. Also, antigen concentration can affect immune response in a biphasic manner: too little or too much can dampen an immune response, so even if the antigen or antigens were known, a typical pharmacologic dose escalation would not follow typical pharmacokinetics. For these reasons, in Protocol 102, 32 patients will have therapy at initial surgery followed by implantation of 20 chambers for a duration of 48 hours. There was a documented increase in tumor infiltrating lymphocytes after treatment in our original trial, this observation provided preliminary supporting evidence that this therapeutic vaccine will elicit an adaptive immune response. Protocol 102 has been designed to further elucidate an immune response with a quantitative assessment of tumor specific T cells as well as circulating M2 macrophages before and after treatment. The design of the Phase 1 trial will allow a statistical analysis of both antigen dose (number of chambers) and time of exposure (chamber dwell time) as either variable may relate to any toxicity or treatment response.
A summary of the treatment paradigm includes: Pre-operative plasma leukopheresis, then surgery with tissue harvest and implantation of 20 diffusion chambers in the rectus sheath with IGF-1R/AS ODN as previously reported within 24 hours of craniotomy, implanted for 48 hours. All patients who meet the eligibility criteria and agree to participate in this study will be potential candidates for therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Documentation by MR of a gadolinium-enhancing intraparenchymal mass consistent with malignant glioma.
- •Frozen section diagnosis of WHO Grade IV glioma, confirmed with permanent section and immunopositive for IGF-1R.
- •An Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 or a Karnofsky Performance Score (KPS) of at least
- •Must be 18 years of age or older.
- •Must sign an approved informed consent.
- •Hemodynamically stable, consistent with Standard of Care values for patients undergoing elective tumor resection.
排除标准
- •Females who are pregnant, nursing, or not inclined to use adequate contraceptive methods if necessary to prevent pregnancy during the study.
- •An active second primary malignancy with the exception of basal cell or squamous cell skin carcinoma.
- •Major concomitant medical illness inclusive of severe chronic obstructive pulmonary disease, multiple sclerosis, symptomatic coronary artery disease, heart failure, recent major cerebrovascular accident, brittle diabetes, renal dialysis, end stage liver disease, labile hypertension, or any autoimmune disorder.
- •A history of heparin-induced thrombocytopenia or hypersensitivity to heparin, enoxaparin, or pork products.
- •An abnormal International Normalized Ratio (INR) of greater than 1.3, if repeatable and refractory to correction by routine methods.
- •Documented deep venous thrombosis
研究组 & 干预措施
Cohort 1
After protocol amendment dated 11 May 2017, all subjects enrolled into the trial will receive 20 chambers for 48 hours.
干预措施: IGF-1R/AS ODN; Surgery with tissue harvest and implantation 20 diffusion chambers in the rectus sheath with IGF-1R/AS ODN within 24 hours of craniotomy, implanted for 48 hours. (Drug)
结局指标
主要结局
Collect adverse events as a measure of safety and tolerability of IG-1R/ AS ODN
时间窗: 36 months
Adverse events and survival outcomes will be captured as a measure of safety and tolerability of IG-1R/AS ODN administered as a treatment 4 to 6 weeks before initiation of standard of care treatment. Blood (equivalent of 8 units of mononuclear cells by plasma leukopheresis) will be collected within 3 days of craniotomy and 7 tbsp of blood on days 14, 28, 42, 56, followed by every 3 months after vaccination to measure the degree of anti-glioma Cytotoxic T lymphoctye immunity achieved.
次要结局
- Document any T-1 weighted MRI-based radiographic responses to treatment.(Evaluated 3 days pre surgery, and again at day 28, day 56, and then every 3 months up to 24 months.)
- Document any T-2 weighted MRI-based radiographic abnormalities or responses to treatment.(Evaluated 3 days pre surgery, and again at day 28, day 56, and then every 3 months up to 24 months.)
- MRI measure of tumor response(Evaluated 3 days pre surgery, and again at day 28, day 56, and then every 3 months up to 24 months.)
研究者
david andrews
Chief, Division of Neuro-Oncology
Thomas Jefferson University